title: Inhibition of NF-κB-induced inflammatory responses by angiotensin II antagonists in aged rat kidney.
abstract: In this study, we explored the mechanisms by which the angiotensin converting enzyme inhibitor (ACEI), enalapril, and the Ang II receptor blocker (ARB), losartan suppress oxidative stress and NF-κB activation-induced inflammatory responses in aged rat kidney. The experimentations were carried out utilizing aged (24-month-old) Brown Norway×Fischer 344 (F1) male rats which were randomized into 3 groups and administered enalapril (40 mg/kg), losartan (30 mg/kg) or placebo for 6 months (daily p.o.). The level of reactive species (RS), peroxynitrite (ONOO(-)), GSH/GSSG and lipid peroxidation were measured. The activity of the pro-inflammatory transcription factor NF-κB, and gene expression of proteins in upstream signaling cascades were measured by electro-mobility shift assay (EMSA) and Western blotting. Enalapril and losartan differentially attenuated redox imbalance and the redox-sensitive transcription factor, the NF-κB pathway. Furthermore, stimulation of the NF-κB activation pathway by phosphorylation of p65 was attenuated by both compounds. Moreover, mediation of phosphorylation of p65 by phosphorylation of IκB kinase αβ (IKKαβ) and mitogen- and stress-activated protein kinase-1 (MSK-1), were also inhibited by enalapril and losartan. Finally, both compounds also lowered expression of NF-κB-dependent inflammatory genes, such as cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS). Only losartan lowered levels of 5-lipoxygenase (5-LOX). These findings indicate that enalapril and losartan differentially suppress inflammatory responses via inhibition of oxidative stress-induced NF-κB activation in aged rat kidney.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Hyoung-Sam
authors.initials: HS
authors.lastname: Heo
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.forename: Byeong Hyeok
authors.initials: BH
authors.lastname: Ye
authors.forename: Young
authors.initials: Y
authors.lastname: Mi Ha
authors.forename: Arnold Young
authors.initials: AY
authors.lastname: Seo
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Christy S
authors.initials: CS
authors.lastname: Carter
mesh_terms: D000375:Aging / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004656:Enalapril / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009393:Nephritis / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D016328:NF-kappa B; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D000804:Angiotensin II; D004656:Enalapril; D019808:Losartan